Cell-based therapies for cancer, involving the adoptive transfer of activated, expanded cells such as T cells, natural killer (NK) cells and dendritic cells (DCs) have proven effective in a variety of settings (K. Palucka et al., Nature reviews. Cancer, 2012, 12: 265-277; D. W. O'Neill et al., Blood, 2004, 104: 2235-2246; A. P. Kater et al., Blood, 2007, 110: 2811-2828; M. Korbling et al., Blood, 2011, 117: 6411-6416). With the emergence of genetically engineered T cells expressing chimeric antigen receptor and other T cell receptors (TCR) (S. A. Grupp et al., N. Engl. J. Med. 2013, 368: 1509-1518; M. Sadelain et al., Cancer Discov., 2013, 3: 388-398; H. Shi et al., Cancer Lett., 2012, 328: 191-197), together with interfering antibodies targeting immune-suppressive molecules, such as PD-1, there is now great interest in cell-based therapies. The efficacy of cell-based therapies, however, relies on the successful migration of cells to their respective targets, tumors, in the case of cytotoxic T cells (CTLs) or NK cells, lymphoid organs, in the case of DC vaccines, and bone marrow (BM), in the case of hematopoietic stem cells. Methods to monitor these transferred therapeutic cells, however, are currently limited, leaving uncertain the fate of these cells in patients and making it difficult to assess the impact of cell modification on trafficking to the target.
None of the current preclinical imaging techniques for tracking cells are ideal for clinical use. Bioluminescence imaging (BLI) using luciferase reporter genes and optical tagging are not practical for whole body imaging because of the limited penetration of light in tissue. Moreover, BLI requires gene transfection and carries the risk of immunogenicity related to exposure to a non-human protein. Magnetic resonance imaging with iron loaded cells has been employed but has limited sensitivity due to negative contrast superimposed on highly heterogeneous background. Radiolabeling of cells has several advantages. Because the body has no background radioactivity, very high label-to-background ratios can be achieved and whole body monitoring is possible. Cell labeling has classically employed 111In-oxine which requires single photon emission tomography (SPECT) imaging (M. L. Thakur et al., J. Lab. Clin. Med., 1977, 89: 217-228; G. McAfee, M. L. et al., J. Nucl. Med., 1976, 17: 480-487; L. Mairal et al., Eur. J. Nucl. Med., 1995, 22: 664-670; R. J. Bennink et al., J. Nucl. Med., 2004, 45: 1698-1704) with its inherently lower sensitivity and resolution compared to positron emission tomography (PET) requiring relatively high radiation doses to the labeled cells. PET is at least ten-fold more sensitive than SPECT and therefore, has the potential to reduce the exposure of labeled cells by at least one log. Fluorine-18-Fluorodeoxyglucose (18F-FDG), a glucose analog, has been used to label cells ex vivo. Because 18F-FDG labeling relies on elevated glucose metabolism, it is not suitable for dormant or inactivated cells. Moreover, the half-life of 18F (109.7 min) significantly limits the amount of time for cell tracking. Finally, 18F-FDG is released from the cells by phosphatase activity (C. Botti et al., Eur. J. Nucl. Med., 1997, 24: 497-504; E. Wolfs et al., J. Nucl. Med., 2013, 54: 447-454) leading to non-specific signals. In order to track cells for at least several days, a positron emitting radioisotope with a longer half-life is required.
Thus, there remains a need in the art for methods for labeling cells with an agent that allows for tracking the cells for at least several days without significantly interfering with cell survival, proliferation, or function.